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NEJM Editorial
To cope with the diagnostic challenges posed by nonclassic cystic fibrosis, a consensus statement has been developed, which defines cystic fibrosis as the presence of a coherent clinical syndrome, plus either evidence of CFTR dysfunction (an abnormal value for sweat chloride or nasal potential difference) or confirmation of cystic fibrosis–causing mutations on both alleles.6 Patients who have disease linked to mutant CFTR with residual protein function but do not meet the diagnostic criteria are considered to have CFTR-related disease. In this issue of the Journal, Groman et al. report extensive genetic analyses of DNA samples from 74 patients with clinical features suggestive of cystic fibrosis.7 Several important observations emerged. First, of the 34 patients in whom standard screening had identified a single cystic fibrosis–causing mutation, most (26) had a second mutation or the IVS8-5T allele, which was discovered by comprehensive sequencing of the CFTR gene. The IVS8-5T allele frequently leads to splicing out of exon 9 of CFTR, which may reduce the function of CFTR protein to a level associated with clinical disease.3,4,5 Thus, in patients with some clinical features that overlap those of cystic fibrosis, plus one CFTR mutation identified by genotype screening, intensive genetic testing of the second allele is likely to identify a second CFTR mutation or polymorphism. Nevertheless, identification of a second mutation or polymorphism in these patients does not conclusively establish the molecular basis of their clinical syndrome. Missense mutations must be validated as disease-causing mutations by testing the prevalence in a large number of non–cystic fibrosis chromosomes or by conducting functional studies, and the effect of the 5T allele must be assessed with the use of functional assays.6 Groman et al. do not report which patients had abnormal values for sweat chloride or nasal potential difference, so it is difficult to determine how many of these patients had cystic fibrosis on the basis of the current diagnostic criteria. Such considerations underscore the limitations of using extensive mutation analysis alone to establish conclusively (or rule out) a diagnosis of cystic fibrosis in unusual cases; extensive clinical and physiological studies are required to complement the genetic data. The second observation is more provocative. In 40 of the 74 patients who underwent extensive genetic testing, standard screening had shown no CFTR mutations. In this group of patients, genetic assays that included Southern blot analysis to detect genomic rearrangements and sequencing of a portion of the promoter region showed two mutant CFTR alleles in only three patients and a single mutation in seven patients. In the other 30 patients, there were no CFTR mutations. The simplest hypothesis is that mutant CFTR was not the basis of the variant clinical syndrome in these 30 patients. The majority of the patients did not undergo extensive testing for evidence of CFTR-mediated abnormalities in ion transport. However, the results of linkage (haplotype) analyses of CFTR and studies of nasal and sweat-gland ion transport in four patients from two families were consistent with this hypothesis. It is not surprising that some patients have a cystic fibrosis–like clinical syndrome ("variant cystic fibrosis") reflecting environmental and genetic influences other than mutations in CFTR,3,8 and some of the patients in the study by Groman et al. may have had such a variant form of the disease. There have been several reports of mutations in different genes that produce similar clinical phenotypes by acting through common pathways in biologic function, including disorders with clinical features that overlap those of cystic fibrosis.9,10,11,12 In the absence of more extensive clinical, radiographic, and physiological information, it is premature to conclude that most (or many) of the patients in this study who did not have any mutations in CFTR had a variant form of cystic fibrosis. Since we cannot rely on molecular testing, a diagnosis of cystic fibrosis must be established by ruling out other disorders, because the clinical phenotype is not sufficiently distinct. Most patients whose DNA was studied by Groman et al. had respiratory symptoms
that are common in the general population (recurrent cough and
wheezing, pneumonia, reactive airway disease, and chronic sinusitis).
These symptoms may be manifestations of a relatively common disorder
(allergic disease or asthma) or a less common disorder (primary
ciliary dyskinesia, postinfectious bronchiectasis,
hypogammaglobulinemia, or The high prevalence of steatorrhea — in 9 of the 30 patients without CFTR mutations — is striking. However, in the absence of a preestablished diagnosis of cystic fibrosis (or any condition known to cause pancreatic insufficiency), studies of fecal fat balance are nonspecific, and the mechanism of excessive fat losses cannot be assigned to maldigestion rather than malabsorption (i.e., a pancreatic cause rather than an intestinal cause). Could some of the patients in this study have had well-defined (but undiagnosed) disorders, such as a gastrointestinal mucosal defect of absorption or the Shwachman–Diamond syndrome, the latter of which is also associated with recurrent respiratory infections? Finally, Groman et al. do not report whether any of the patients had abnormalities that are also linked to slight increases in sweat chloride values, such as malnutrition, adrenal abnormalities, or the skin changes associated with disorders such as hypogammaglobulinemia.15 Thus, a cystic fibrosis–like constellation of signs and symptoms may reflect, directly or indirectly, the effects of several recognized clinical disorders and their consequences, and labeling such a constellation "variant cystic fibrosis" is a concern. In theory, some patients may have a variant form of cystic fibrosis without mutations in the CFTR gene, although such an entity will be difficult to define, unless an alternative genetic cause is identified, perhaps coupled with diagnostic abnormalities of ion transport. The study by Groman et al. highlights the potential importance of the findings in such patients, which provide an opportunity to gain further insight into mechanisms underlying the pathobiology of the cystic fibrosis phenotype. The study also underscores the challenges encountered in the pursuit of novel pathophysiological insights. These effects will require not only molecular analyses, but also intensive evaluation of patients with the use of standard clinical, radiographic, and biochemical techniques. Moreover, we must broaden our approaches to evaluating ion transport in vivo and use evolving methods (proteomics) to identify biomarkers of other nearly unique features of cystic fibrosis. We look forward to further definition of the clinical and biologic phenotype in patients such as those described by Groman et al.
References
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-antiprotease
deficiency) that might be present in this highly selected group of
patients. Nor can we rely on the sweat chloride test to confirm the
diagnosis. The patient population in the study by Groman et al. was
preselected, in part, on the basis of borderline or abnormal sweat
chloride values, and there is substantial test and biologic
variability in sweat chloride values, particularly those in the
borderline range, among normal persons.